Lung Epithelial Healing: A Modified Seed and Soil Concept

Abstract

Airway epithelial healing is defined as restoration of health or soundness; to cure. Our research indicates that two types of progenitor cells participate in this process: the tissue-specific stem cell (TSC) and the facultative basal progenitor (FBP). The TSC restores the epithelium to its normal structure and function. Thus, the TSC regenerates the epithelium. In contrast, the FBP-derived epithelium is characterized by regions of cellular hyperplasia and hypoplasia. Since the FBP-derived epithelium deviates from normal, we term the FBP-mediated process repair. Our work indicates that the TSC responds to signals from other epithelial cells, including the FBP. These signals instruct the TSC to proliferate or to select one of several differentiation pathways. We interpret these data in the context of Stephen Padget's "seed and soil" paradigm. Therein, Padget explained that metastasis of a tumor, the seed, to a specific site, the soil, was determined by the growth and differentiation requirements of the tumor cell. By extending the seed and soil paradigm to airway epithelial healing, we suggest that proliferation and differentiation of the TSC, the seed, is determined by its interactions with other cell types, the soil. Based on this concept, we provide a set of suggestions for development of cell-based therapies that are directed toward chronic airways disease.

An Official American Thoracic Society Workshop Report: Stem Cells and Cell Therapies in Lung Biology and Diseases

“…Despite suggested guidelines from previous conferences and from other sources, precise definitions and characterizations of specific cell populations, notably the putative endogenous cell populations in the lung as well as MSCs and EPCs, are not agreed on. In many respects this reflects more sophisticated knowledge and increasing appreciation that the phenotypic and functional attributes of cells are context dependent (12)(13)(14)(15)(16)(17)(18)(19). Cells previously considered to be differentiated airway or alveolar epithelial cells can proliferate and differentiate into other lung epithelial cell types under varying circumstances.…”

“…A number of themes emerged during these presentations that suggest a consensus has now been reached regarding several salient points in lung progenitor cell biology. These include the observation that both epithelial and mesenchymal compartments contain multiple cell types that can be classified as "endogenous progenitor cells," that lung injury models are often needed to interrogate the growth and differentiation potential of individual progenitors, and that both the type and severity of lung injury are of paramount importance in determining lung repair outcomes (12)(13)(14)(15)(16)(17)(18)(19). Emerging themes included the growing recognition that epithelial-mesenchymal interactions are not only important during lung development but remain relevant for maintaining adult lung homeostasis, repair, and regeneration and that these are functionally distinct processes that likely involve different cell populations and signaling pathways.…”

“…Significant progress also continues to be made in investigations of local (endogenous) stem and progenitor cells resident in adult lungs. Advances in lineage tracing approaches and other techniques continue to provide important insights into understanding of the identity and lineage expansion properties of previously identified putative endogenous stem and progenitor populations and suggest an increasingly complex network of cellular repair after injury (reviewed in [12][13][14][15][16][17][18][19]). Recent data have broadened this beyond consideration of epithelial progenitors to also include endogenous pulmonary vascular and interstitial progenitors (20)(21)(22).…”

Repair of the airway epithelium after chlorine-induced injury.

“…High-level chlorine exposure results in sloughing of the pseudostratified airway epithelium of the proximal airways composed primarily of secretory, ciliated, and basal cells [25,26,29]. Repair of the airways after injury involves the coordinated action of local progenitor cells and stem cells to restore the integrity of the epithelium [46,47,69].…”

“…Although the identity of tissue-specific stem cells in the airways is not completely established, current evidence suggests that subsets of basal cells and Clara cells function as stem cells for repair and long-term maintenance of the tracheobronchial and bronchiolar epithelium, respectively [49,51,53,70,71]. In the mouse tracheobronchial epithelium, most basal cells express the cytoskeletal protein keratin 5 (K5) whereas only a subset of these cells express keratin 14 (K14) during steady state [45, 49,69]. Lineage-tracing studies show that both K5-and K14-expressing basal cells are capable of extensive self-renewal and differentiation into ciliated and Clara cells [50,52].…”